Synaptic plasticity, the change in the strength of neuronal connections in the brain, is thought to underlie memory storage and may play a crucial role in a variety of neurological and mental disorders, including Alzheimer's disease, mental retardation, epilepsy and depression. One form of synaptic plasticity that has received much attention is long-term potentiation (LTP), an activity-dependent form of synaptic enhancement. Like many forms of memory and synaptic plasticity, LTP in the hippocampus has distinct temporal phases. Long-lasting LTP differs from short-term potentiation in requiring protein kinase A (PKA) activity, protein synthesis and transcription. To explore the molecular basis and behavioral significance of long-lasting forms of synaptic plasticity, we have produced mice in which PKA activity in the hippocampus is reduced by the transgenic expression of R(AB), a dominant negative form of the regulatory subunit of PKA. R(AB) transgenic mice exhibit selective impairments in long-term contextual memory and long-lasting forms of hippocampal synaptic plasticity. In this proposal, we outline a series of genetic, pharmacological, biochemical and molecular experiments to examine the role that PKA plays in hippocampal function. In Specific Aim 1, we will use pharmacological and biochemical approaches to define the role that PKA plays in memory consolidation. Our initial characterization of the R(AB) transgenic animals has revealed deficits in contextual fear conditioning and spatial memory after massed training. In Specific Aim 2, we will determine if memory deficits in the R(AB) transgenic mice can be overcome by increasing the number of training trials or altering the training schedule. Specific Aim 3 will determine if PKA plays a general role in hippocampal function by examining the performance of R(AB) transgenic mice in non-spatial tests of hippocampal function using tasks such as social transmission of food preferences and object recognition. The critical molecular targets of PKA and the identity of genes whose expression is regulated by this signal transduction pathway during memory storage remain crucial open questions, and these studies are the focus of Specific Aim 4. With the combination of genetic, molecular and pharmacological studies outlined in this grant proposal, we hope to determine the molecular basis of long-term memory storage and define the role that PKA plays in synaptic plasticity and long-term memory.